1. Field of the Invention
The present invention refers to a process for preparing the [R—[R*,R*-(E)]]-2,2′-(1,8-dioxo-4-octene-1,8-diyl) bis(oxy-3,1-propanediyl) bis(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]isoquinolinium)dichloride, commonly known as mivacurium chloride, having the following formula:

2. Discussion of the Background Art
Mivacurium chloride is a rapid, non-depolarising, neuromuscular blocking agent of short duration, used therefore as anesthetic, to provide skeletal muscle relaxation in minor surgical operations, in emergency surgical procedures of short to intermediate duration and during intubation of the trachea.
As it is evident from the formula above reported, mivacurium chloride contains a chiral center at the C(1) and C(1′) carbon atoms and, at each center, may therefore exist either the R or the S configuration. Moreover, the methyl substituents on each of the two quaternary nitrogen atoms may exist in either the R or the S configuration.
The compound having the R configuration at both chiral centers is known to be free from significant side effects at the normal dosages. In view of what explained above, this compound may exist in three diastereoisomers: the trans-trans (1R, 1′R; 2S, 2′S); the cis-trans (1R, 1′R; 2R, 2′S), and the cis-cis diastereoisomer (1R, 1′R; 2R, 2′R). The trans-trans and the cis-trans diastereoisomers have neuromuscolar blocking potencies not significantly different from each other, whereas the cis-cis diastereoisomer has been estimated to have approximately one tenth the neuromuscolar blocking potency of the other two diastereoisomers.
Mivacurium chloride has been disclosed for the first time in U.S. Pat. No. 4,761,418, together with a process for preparing it. As far as the Applicant is aware, the process disclosed in U.S. Pat. No. 4,761,418 is the only process for the preparation of mivacurium chloride known in the art, and it consists in the coupling of (E)-4-octene-1,8-dioic acid dichloride with the isochinolinic derivative of formula (A), hereinafter referred to as compound A and whose chemical name is N-3-hydroxypropyl-1-(R)-5′-methoxylaudanosinium chloride, in warm 1,2-dichloroethane:

According to U.S. Pat. No. 4,761,418, once the coupling reaction is complete, the solvent is removed by distillation under vacuum and replaced by chloroform. The so obtained chloroformic solution is then washed with diluted aqueous solutions of sodium chloride to eliminate the isochinolinic compound A in excess, and the organic solvent is removed by distillation under vacuum, thus obtaining an amorphous solid. This solid product is then purified from impurities by washings with warm 2-butanone, removing then the residual organic solvent by distillation under vacuum. Finally, the amorphous solid product is dissolved in methanol, filtered and freeze-dried, thus yielding the mivacurium chloride.
Substantially the same synthesis has been disclosed also in Current Medicinal Chemistry, vol. 9, Nov. 16, 2002.
A fundamental limitation of this process consists in that the raw product obtainable by the above said process contains a high amount of various impurities, mainly represented by the compound A used as starting material both as cis and trans diastereoisomer, and by the following product, so called “acid ester”, both as cis and trans diastereoisomer:

Due to the pharmaceutical use of mivacurium chloride, it is of paramount importance to have available a process for the purification of this product. But the purification of the raw product in the form of an amorphous solid, as disclosed in U.S. Pat. No. 4,761,418, is difficult on the operational front: the amorphous solid to be treated with organic solvents is actually a gummy product, not miscible with the proposed organic solvent. Therefore, for this treatment to be efficacious, it must be repeated so many times that it is not economically practicable, and cannot be scaled up.
It is therefore still felt the need of developing a scalable process for preparing mivacurium chloride having a high purity degree, that does not show the drawbacks highlighted above for the known process.